Recursive Partitioning Analysis Class Research Articles

Initial Treatment Response Is Prognostic and Predictive of Relapse Patterns: Outcomes of >500 Patients Treated for Primary CNS Lymphoma

Introduction: Given concerns for neurotoxicity of standard dose (SD) whole brain radiotherapy (WBRT) after high-dose methotrexate (MTX), consolidation for primary CNS lymphoma (PCNSL) has evolved to either autologous hematopoietic cell transplantation (AHCT) or reduced dose (RD; ≤24Gy) WBRT with cytarabine. We sought to evaluate factors influencing consolidation approach and survival outcomes by consolidation strategy. For a disease that has historically been considered multifocal, we analyzed patterns of relapse in a large cohort of contemporarily treated patients. Methods: PCNSL patients treated at Memorial Sloan Kettering from 1983-2020 were analyzed. Initial site was determined by T1 post-contrast-enhancing MRI. Patients were categorized by response (complete/unconfirmed [CR/CRu], partial [PR], stable, progression [POD]) to induction and consolidation (AHCT, RD vs SD WBRT, cytarabine, other). Factors impacting consolidation strategy were assessed by multinomial logistic regression models. Site of initial progression was categorized as local (involving/adjacent to initial site) vs distant intraparenchymal, leptomeningeal (CSF and/or MRI), or other. Cumulative incidence of local failure was assessed with death as a competing risk. Progression-free survival (PFS) was assessed from consolidation start with Kaplan Meier and proportional hazards. Results: Of 645 patients, 559 were eligible for inclusion (diffuse large B-cell, sufficient data, ≥1 MRI response assessment). Median follow-up was 7.4 years. From diagnosis, median PFS was 2.2 years and median overall survival (OS) was 5.7 years. Median age was 63 years (IQR 54-72), and most (57%) were recursive partitioning analysis (RPA) class 2 (age≥50, KPS≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received MTX-based induction (532, 95%); common regimens were rituximab, MTX, procarbazine, vincristine (R-MVP; 257, 46%) and MVP (144, 26%). Most (403, 72%) responded to induction (305 [76%] CR/CRu, 98 PR [25%]). 385 patients received consolidation: 116 (21%) WBRT, of which 55 (47%) had RD; 80 (15%) AHCT; 170 (31%) cytarabine; 19 (3%) other. Consolidation approaches evolved over time (SD WBRT 65% in 1980s-1990s vs 3% in 2000s-2020s, RD WBRT 0% in 1980s-1990s vs 18% in 2000s-2020s, AHCT 4% in 1980s-1990s vs 25% in 2000s-2020s; Fisher's exact test, p-value <0.001). RPA and induction response were significantly associated with consolidation approach, while baseline tumor size and leptomeningeal involvement were not. Patients with higher RPA were less likely to undergo AHCT than RD WBRT (RPA 3 vs 1, HR 0.15 [0.04, 0.53], p=0.003). Compared to patients with CR, those with PR were more likely to receive SD WBRT (HR 4.56 [1.70, 12.3] p=0.003) and less likely to receive AHCT (HR 0.34 [0.13, 0.93] p=0.036) than RD WBRT. Of the 385 patients consolidated, 352 (91%) achieved CR/CRu, of whom 145 (41%) later relapsed. Most relapses after CR to consolidation were multifocal, non-local (1- and 5-year cumulative incidences: 43% and 86%, respectively) as opposed to unifocal local (8% and 16% at 1- and 5-years) or unifocal non-local (31% and 70% at 1- and 5-years). Upon controlling for diagnosis year, induction regimen, RPA, consolidation approach, and the interaction between consolidation and RPA, there was no significant difference in PFS or OS by consolidation strategy (AHCT vs RD WBRT: PFS HR 1.25 [0.31, 5.05], p=0.755; OS HR 0.88 [0.36, 2.19], p=0.788; Figure). Among those who did not achieve CR to consolidation (POD n=16, PR n=14, stable n=4), patients who progressed had the worst prognosis (median OS: POD 1.04 years, PR 2.7 years, Stable 6.1 years; p=0.005) with 6 (38%) experiencing local only progression. Of the 81 patients with POD on induction, 46 (57%) had local only progression. Conclusion: In a large PCNSL cohort, modern consolidation (AHCT, RD WBRT) achieved similar survival outcomes upon controlling for clinical variables in patients who achieved CR to consolidation. Performance status, age, and response to induction influenced consolidation strategy and outcomes, suggesting a role for further personalization. While delayed relapses after achieving CR to consolidation were often multifocal and non-local, early progression patterns in refractory patients (with many remaining localized) may suggest a role for focal RT for residual disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multi-Institutional Datasets Validate the Recursive Partitioning Analysis for Overall Survival in Patients Undergoing Spine Radiosurgery for Spine Metastasis

<h3>Purpose/Objective(s)</h3> The recently published spine radiosurgery (sSRS) recursive partitioning analysis (RPA) for overall survival (OS) separated patients into 3 distinct prognostic groups. We sought to externally validate this RPA using a multi-institutional dataset. <h3>Materials/Methods</h3> A total of 444 patients were utilized to develop the recently published sSRS RPA predictive of OS in patients with spine metastases. The RPA identified three distinct prognostic classes. RPA Class 1 was defined as KPS >70 and controlled systemic disease (n=142); RPA Class 2 was defined as KPS>70 with uncontrolled systemic disease or KPS ≤70, age ≥54 and absence of visceral metastases (n=207); RPA Class 3 was defined as KPS ≤70 and age <54 years or KPS≤70, age ≥54 years and presence of visceral metastases (n=95). We utilized data from large tertiary care centers to validate this RPA. A total of 749 patients were in the validation cohort and were divided based on their RPA Class. Kaplan-Meier method was used to estimate OS and log-rank test was used to compare OS between RPA classes. <h3>Results</h3> In the validation cohort (749 patients), the median OS was 11.0 months. One-hundred-thirteen (15.1%) patients were in RPA Class 1, 432 (57.7%) patients in RPA Class 2 and 204 (27.2%) patients in RPA Class 3. The median OS in the validation cohort based on RPA Class was 27.1 months for Class 1, 13.0 months for Class 2 and 3.5 months for Class 3. Patients in RPA Class 1 had a significantly better OS compared to those in Class 2 of the validation cohort (p<0.01). Similarly, patients in RPA Class 2 had a significantly better OS compared to those in Class 3 (p<0.01). <h3>Conclusion</h3> The external datasets from two large centers validated the spine SRS RPA successfully for RPA for OS for patients undergoing sSRS for spinal metastases. This is the first RPA for OS to have been externally validated using a large dataset. Based on this validation, upfront spine SRS is strongly supported for patients in RPA Class 1. Upfront SRS is also supported for RPA Class 2 patients. Patients in RPA Class 3 would benefit most from upfront conventional radiotherapy given their poor expected survival. Given successful external validation, this RPA helps guide physicians to identify those patients with spinal metastases who most benefit from sSRS.

Outcomes and Failure Patterns for >500 Patients Treated for Primary CNS Lymphoma: Exploring Modern Roles for Radiotherapy

<h3>Purpose/Objective(s)</h3> Given concerns for neurotoxicity of standard dose (SD) whole brain radiotherapy (WBRT) after high-dose methotrexate (MTX), consolidation for primary CNS lymphoma (PCNSL) has evolved to either autologous stem-cell transplant (ASCT) or reduced dose (RD; <24Gy) WBRT. We analyzed outcomes and failure patterns by consolidation strategy in the largest cohort of contemporarily treated patients. <h3>Materials/Methods</h3> PCNSL patients treated from 1983-2020 were analyzed. Initial T1 post-contrast-enhancing disease was characterized by site. Patients were stratified by response (complete [CR], partial [PR], stable, progression) to induction and consolidation (ASCT, RD vs SD WBRT, cytarabine, other). Site of initial progression was characterized as local (involving/adjacent to initial site) vs distant intraparenchymal, leptomeningeal (CSF and/or MRI), or other. Progression-free survival (PFS) was assessed from diagnosis using Kaplan Meier and proportional hazards. Logistic regression was used to evaluate associations with local failure. <h3>Results</h3> Of 645 patients, 564 were eligible (diffuse large B-cell, sufficient data, ≥1 MRI response assessment). Median follow-up was 2.7 years (IQR 1.2-5.6). Median age was 63 (range 19-90), and most (57%) were recursive partitioning analysis (RPA) class 2 (age≥50, KPS≥70). Most had supratentorial (423, 81%), multifocal (276, 54%), bilateral (225, 43%), and deep structure involvement (310, 56%). Most received MTX-based induction (536, 95%); common regimens were rituximab, MTX, procarbazine, vincristine (R-MVP; 253, 45%) and MVP (144, 26%). Most (412, 73%) responded to induction (225 CR, 187 PR). 385 patients were consolidated: 116 (30%) WBRT, of which 55 (47%) had RD; 81 (21%) ASCT; 175 (45%) cytarabine; 13 (3%) other. Consolidation approach changed over time (SD WBRT earlier vs RD WBRT and ASCT recently). RPA differed by consolidation (93% of ASCT vs 75% of RD WBRT had RPA 1-2; chi square p=0.02). Of those consolidated, 344 (89%) achieved CR, of whom 141 (41%) later relapsed, mostly non-locally (132, 94%) without maintaining laterality or focality. Early progression on induction or consolidation was more likely local compared to later relapses (OR 12.9 95%CI 6.4-25.9; p<0.001). Median PFS among those with CR was 4.9 years (95%CI 3.6-6.0) and differed by consolidation (log-rank p<0.001): ASCT 9.8 years (95%CI 7.5-NR); RD WBRT 7.6 years (95%CI 4.4-13.2); SD WBRT 4.2 years (95%CI 2.7-7.4); cytarabine 2.8 years (95%CI 2.2-3.7). Among those with RPA 1-2, there was no PFS difference between ASCT and RD WBRT (HR 0.74 95%CI 0.38-1.43). <h3>Conclusion</h3> In a large PCNSL cohort, modern consolidation (ASCT, RD WBRT) had similarly improved PFS vs SD WBRT or no RT. Performance status and age influenced consolidation strategy and outcomes, suggesting a role for further personalization. Early progression patterns may reveal a role for focal RT for residual disease. Future analyses will focus on the relationship between consolidation strategy and failure patterns.

Incidence and clinical profile of brain metastasis treated with whole brain radiotherapy in a tertiary hospital in eastern India: A retrospective audit.

Management of brain metastases (BM) is witnessing marked advancement worldwide and modern technologies with better outcomes are gradually being adopted in developing countries. However, data regarding current practice in this field is lacking from the Indian subcontinent prompting us to plan the current study. A retrospective, single institutional audit was performed on 112 patients with solid tumors metastasizing to the brain treated over the last 4 years at a tertiary care center in eastern India, of which 79 were ultimately evaluable. Demography, patterns of incidence, and overall survival (OS) were determined. The prevalence of BM was 5.65% among all patients with solid tumors. The median age was 55 years with a slight male preponderance. Lung followed by breast were the most common primary subsites. Multiple BM (54%), left-sided (61%), and frontal lobe lesions (54%) were the more common. Metachronous BM was found in 76% of patients. All patients received whole brain radiation therapy (WBRT). The median OS for the entire cohort was 7 months (95% confidence interval [CI]: 4 - 19 months). The median OS for lung and breast primaries were 6.5 and 8 months and for recursive partitioning analysis (RPA) classes I, II, and III the OS were 11.5, 7, and 3 months, respectively. Median OS did not differ by number of or other sites of metastases. The outcomes from our series about BM from solid tumors in patients from eastern Indian are in congruence to those available in the literature. Patients with BM are still largely treated with WBRT in resource-limited settings.

Influence of temporal muscle thickness on the outcome of radiosurgically treated patients with brain metastases from non-small cell lung cancer.

The purpose of this study was to assess the impact of temporal muscle thickness (TMT), a surrogate marker for sarcopenia, in radiosurgically treated patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC). For 566 patients with BMs from NSCLC in the period between June 2012 and December 2019, TMT values were retrospectively measured on the planning brain magnetic resonance imaging (MRI) studies that had been obtained before their first Gamma Knife radiosurgery treatment (GKRS1). Predefined sex-specific TMT cutoff values were used to stratify the study cohort into patients at risk for sarcopenia and patients with normal muscle status. Cox regression models adjusted for other prognostic parameters were used to evaluate sarcopenia as an independent prognostic factor. In sarcopenia patients with a TMT below the sex-specific cutoff values, the risk of death was significantly increased (HR 1.908, 95% CI 1.550-2.349, p < 0.001). In addition, sarcopenia was revealed as an independent prognostic factor even after adjusting for age groups, sex, number of BMs, presence of extracranial metastases, NSCLC subtypes, Karnofsky Performance Status groups, recursive partitioning analysis classes, and concomitant immunotherapy or targeted therapy (HR 1.680, 95% CI 1.347-2.095, p < 0.001). However, patients at risk for sarcopenia showed no significant differences in the estimated mean time until local BM progression after GKRS1, compared to patients with normal muscle status (p = 0.639). TMT obtained from planning MRI studies is an independent prognostic marker in radiosurgically treated patients with BMs from NSCLC and may aid patient stratification in future clinical trials.

Real-world analysis of different intracranial radiation therapies in non-small cell lung cancer patients with 1–4 brain metastases

PurposeStereotactic radiosurgery (SRS) has become a standard approach for the treatment of patients with few metastatic brain lesions. However, the optimal treatment approach for the use radiotherapy in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) remain unclear. This study aimed to compare the survival outcomes and intracranial local control in NSCLC patients with 1–4 BMs who are treated with SRS using linear accelerators (LINAC-SRS), whole-brain radiotherapy (WBRT), or WBRT plus radiotherapy boost (WBRT + RTB).Materials and methodsWe retrospectively analyzed 156 NSCLC patients with 1–4 BMs who received LINAC-SRS, WBRT, and WBRT + RTB. The median overall survival (OS), intracranial progression-free survival (iPFS), and distant brain failure-free survival (DBF-FS) and related prognostic factors were analyzed.ResultsThe median follow-up period was 31.6 months. The median OS times in the LINAC-SRS, WBRT, and WBRT + RTB groups were not reached, 33.3 months and 27.9 months, respectively. The difference in survival rate was non-significant (P = 0.909). The 2-year iPFS and DBF-FS rates in the LINAC-SRS, WBRT and WBRT + RTB groups were 51.6% and 37.5%; 42.0% and 50.4%; and 51.1% and 56.1%, respectively. There was no significant difference in 2-year iPFS or DBF-FS among the three groups (P = 0.572 for iPFS, P = 0.628 for DBF-FS). Multivariate analysis showed that the independent adverse prognostic factors for OS, iPFS, and DBF-FS were neurological symptoms, recursive partitioning analysis (RPA) class, and targeted therapy.ConclusionLINAC-SRS did not result in significantly superior survival times or intracranial local control compared to WBRT or WBRT + RTB in the treatment of NSCLC patients with 1–4 BMs.

Risk Stratification to Define the Role of Radiotherapy for Benign and Atypical Meningioma: A Recursive Partitioning Analysis.

The role of adjuvant radiotherapy (RT) for benign or atypical meningioma is controversial. To identify prognostic factors and a subgroup that could be potentially indicated for adjuvant RT. A total of 336 patients with benign and 157 patients with atypical meningioma underwent surgical resection between January 2015 and December 2019. We retrospectively analyzed 407 patients who did not receive adjuvant RT to stratify risk groups for recurrence. A recursive partitioning analysis (RPA) with the prognostic factors for their failure-free survival (FFS) divided the patients into risk groups. The 3-year FFS with surgical resection only was 76.5%. Identified prognostic factors for FFS were skull base location, tumor size, brain invasion, a Ki-67 proliferation index of ≥5%, and subtotal resection. The RPA-classified patients were divided into 4 risk groups: very low, low, intermediate, and high, and their 3-year FFS were 98.9%, 78.5%, 59.8%, and 34.2%, respectively. Intermediate-risk and high-risk groups comprise the patients with meningioma of sizes ≥2 cm after subtotal resection or meningioma of sizes >3 cm, located in the skull base or with brain invasion, respectively. After combining with patients treated with adjuvant RT, no FFS benefit was found in the very low-risk and low-risk groups after adjuvant RT, whereas significantly improved FFS was found in the intermediate-risk and high-risk groups (P < .05). The RPA classification revealed a subgroup of patients who could be potentially indicated for adjuvant RT even after gross total resection or for whom adjuvant RT could be deferred.

Cranial Radiotherapy for Prostate Cancer Patients With Brain Metastases Inaccessible to Stereotactic Radiotherapy.

To evaluate patients and treatment characteristics as well as clinical outcome in patients with intracranial metastases from prostate cancer (PCA) treated with palliative radiotherapy. Fifteen patients treated for intracranial metastases of PCA were identified. The median age of patients was 69 years. 80% of patients received whole brain radiotherapy and 20% received partial brain radiotherapy. Clinical outcome was assessed. Univariate analysis was performed to analyze the impact of patient specific parameters on survival. There was no >G2 acute or any late toxicity. Median time from the first diagnosis of PCA to first diagnosis of intracranial metastases was 62 months (range=15-160 months). Median survival from first diagnosis of intracranial metastases was 14 weeks (range=0-126 weeks) and 6 weeks (range=0-47 weeks) from the start of radiotherapy. In univariate analysis, survival was significantly better for patients with an Eastern Cooperative Oncology Group (ECOG) performance status 1 compared to ECOG 2-3 [18 weeks (range=5-47 weeks) vs. 3 weeks (range=0-21 weeks), p=0.030] and Recursive Partitioning Analysis (RPA) class 2 compared to RPA class 3 [18 weeks (range=5-47 weeks) vs. 6 weeks (range=0-21 weeks), p=0.045]. Overall survival of the patients with wide-spread intracranial metastases from PCA was poor. The decision for a radiotherapy should be done on individual patient basis.

Stereotactic radiosurgery for brain metastases from pelvic gynecological malignancies: oncologic outcomes, validation of prognostic scores, and dosimetric evaluation

IntroductionStereotactic radiosurgery is a well-established treatment option in the management of brain metastases. Multiple prognostic scores for prediction of survival following radiotherapy exist, but are not disease-specific or validated for...

Establishing the utility of Recursive Partitioning Analysis for patients with intra-cranial metastases managed in a KwaZulu-Natal state sector Oncology unit

Background: Brain metastases are relatively common and carry a poor prognosis. In a resource-constrained environment, the judicious use of radiotherapy must be considered in the context of its benefit. The Recursive Partitioning Analysis (RPA) scoring system is internationally validated to predict median survival in patients with brain metastases. It may be used to guide appropriate management of patients with brain metastases.Aim: To establish the relevance of applying the RPA prognostic scoring system to the local setting.Setting: The Department of Oncology, Greys Hospital, Pietermaritzburg, South Africa.Methods: A retrospective chart review of patients treated for brain metastases for the period 01 January 2014 to 31 December 2019 was performed. Data was collected to determine the RPA class for each patient. Multivariate analysis of potential factors which could impact survival was done, and the actual survival of each patient was calculated.Results: The commonest primary cancer in the study cohort was breast (67%), followed by lung (17%). Survival differences between RPA classes were statistically significant (p 0.001). Actual survival relative to that predicted by the RPA model was 4.5 versus 7–12 months, 3.6 versus 4–7 months, and 0.8 versus 2–4 months, for classes I, II and III, respectively.Conclusion: Results support the use of the RPA classification to risk stratify patients in this setting – and therefore may be used in treatment decision-making. However, it over-predicts the median survival for the local population. Larger studies are warranted in diagnostically homogenous patient groups with brain metastases, to determine survival more accurately.

Novel prognostic classification predicts overall survival of patients receiving salvage whole-brain radiotherapy for recurrent brain metastasis from breast cancer: A recursive partitioning analysis (KROG 16-12)

BackgroundTo investigate outcomes of salvage whole-brain radiotherapy (WBRT) for recurrent brain metastases (BM) from breast cancer (BC), to identify prognostic factors of overall survival (OS), and to propose a novel prognostic classification for OS in these patients. Materials and methodsWe identified 54 patients who had received salvage WBRT as the second brain-focused treatment for recurrent BM from BC (2000–2014). The median follow-up duration was 4.9 months. A recursive partitioning analysis (RPA) was conducted to develop a model to predict OS at the time of salvage WBRT. ResultsThe median OS was 6.8 months. OS according to BC-specific graded prognostic assessment (breast-GPA), modified breast-GPA, and updated breast-GPA did not represent our cohort. In the multivariate analysis, a long time before salvage WBRT (≥16 months), control of primary BC or extracranial metastases, systemic treatment after salvage WBRT, and administration of a biologically effective dose for an α/β of 10 Gy (BED10) of salvage WBRT >37.5 Gy showed superior OS. We proposed three RPA classes based on the control of both primary BC and extracranial metastasis and BED10 of salvage WBRT: class I, class II, and class III. In this model, patients with class I experienced the best OS (34.6 months; class II, 5.0 months; class III, 2.4 months; P < 0.001). ConclusionsIn our RPA classification according to the control of both primary BC and extracranial metastasis and the dose of salvage WBRT, significant differences in OS were observed. The subsequent use of a systemic treatment showed better OS.

Predictors of Recurrence and Survival in High-Stage Primary Cutaneous Squamous Cell Carcinoma: A Recursive Partitioning Analysis

<h3>Purpose/Objective(s)</h3> High stage cutaneous squamous cell carcinoma (CSCC) has an elevated risk of recurrence (5-25%). Current staging systems stratify patients rely on tumor factors only. We sought to develop an RPA incorporating patient-, tumor-, disease-, and treatment-related factors to identify prognostic subgroups for high-stage CSCC patients receiving definitive therapy. <h3>Materials/Methods</h3> All high-stage CSCCs, defined as Brigham & Women's Hospital (BWH) tumor (T) staging system T2B and T3, treated with curative intent were included. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log rank test. Recursive partitioning analysis (RPA) was performed to identify prognostic factors for RFS and OS. <h3>Results</h3> A total of 444 patients (76% male, 95% Caucasian, median age 74 years) with 523 primary tumors were included. Median follow up was 31 months (range 1-194). 31% of patients were immunosuppressed (organ transplant 13%, chronic lymphocytic leukemia (CLL) 14%, and other reasons 3%). 432 tumors were BWH T2b and 91 were BWH T3, of whom 12% were node-positive, 32% node-negative, and 56% unknown nodal status. 33% of patients experienced recurrence. Immunosuppression, recurrent tumor, perineural invasion (PNI), and lymphovascular space invasion (LVSI) were associated with significantly worse RFS (median RFS 23 months, 95% CI, 19-28), while immunosuppression, lymph node positivity, and extranodal extension (ENE) were associated with significantly worse OS (median OS 40 months, 95% CI, 33-46). RPA identified 4 prognostic subgroups with distinct RFS patterns (<i>P</i> < 0.0001): class I included age < 77 years without LVSI (N = 212, 2-year RFS: 63%; 95% CI, 56-70%), class II included age ≥ 77 years without PNI (N = 132, 2-year RFS: 44%, 95% CI, 36-55%), class III included age < 77 years with LVSI (N = 36, 2-year RFS: 29%; 95% CI, 17-50%), and class IV included age ≥ 77 years with PNI (N = 60, 2-year RFS: 25%; 95% CI, 15-41%). RPA identified 4 prognostic subgroups with distinct OS patterns (<i>P</i> < 0.0001): class I included age < 78 years and ≤ 1 lymph node positive (N = 221, 2-year OS: 84%; 95% CI, 79-90%), class II included age ≥ 78 years and no or immunosuppression other than CLL (N = 141, 2-year OS: 64%; 95% CI, 55-73%), class III included age < 78 years and > 1 lymph node positive (N = 48, 2-year OS: 54%; 95% CI, 41-71%), and class IV included age ≥ 78 years and immunosuppression from CLL (N = 34, 2-year OS: 37%; 95% CI, 23-57%). <h3>Conclusion</h3> An RPA classification system was created for patients with high-stage primary CSCC treated with definitive intent that identifies 4 prognostic subgroups associated with recurrence-free survival and overall survival based on age, LVSI, PNI, burden of nodal metastasis, and immunosuppression status. This has implications for patient counselling, clinical trial design and post-treatment surveillance.

Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

The association between levetiracetam and survival with isocitrate dehydrogenase (IDH) wild-type glioblastomas is controversial. We investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affects overall survival (OS) of patients with IDH wild-type glioblastoma. In this observational single-institution cohort study (2010-2018), inclusion criteria were (1) age ≥18 years; (2) newly diagnosed supratentorial tumor; (3) histomolecular diagnosis of IDH wild-type glioblastoma; and (4) standard chemoradiation protocol. To assess the survival benefit of levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class, tumor location, preoperative volume, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Patients with unavailable O6-methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. A total of 460 patients were included. The median OS was longer in the 116 patients with levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95% confidence interval [CI] 17.2-24.0) than in the 126 patients with part-time levetiracetam use (16.8 months; 95% CI 12.4-19.0) and in the 218 patients who never received levetiracetam (16.0 months; 95% CI 15.5-19.4; p = 0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.93; p = 0.014), MGMT promoter methylation (aHR 0.53; 95% CI 0.39-0.71; p < 0.001), and gross total tumor resection (aHR 0.57; 95% CI 0.44-0.74; p < 0.001) were independent predictors of longer OS. After case matching (n = 54 per group), a longer OS was found for levetiracetam use during the whole duration of the standard chemoradiation protocol (hazard ratio 0.63; 95% CI 0.42-0.94; p = 0.023). Levetiracetam use during the whole standard chemoradiation protocol possibly improves OS of patients with IDH wild-type glioblastoma. It should be considered in the antitumor strategy of future multicentric trials. This study provides Class III evidence that in individuals with IDH wild-type glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median OS.

A Prognostic Index for Predicting Survival of Patients Undergoing Radiation Therapy for Spine Metastasis Using Recursive Partitioning Analysis.

Background: Physicians' estimate of life expectancy in patients with spine metastasis frequently impacts treatment decisions regarding surgery, radiation techniques, dose, and fractionation. Objective: We aimed to identify predictors of survival and generate a stratification schema that could guide clinical decision making. Materials and Methods: We identified 269 patients who have undergone surgery and/or radiation for spine metastasis from 2002 to 2013 at an academic medical institution in the United States. A univariate survival analysis was carried out using the Kaplan-Meier method. Differences in survival by histology were assessed using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model, then using the same variables, recursive partitioning analysis (RPA) was conducted to determine risk groups associated with survival. Results: The median overall survival was 4.76 months. Twenty percent, 40%, and 57% of patients died within one, three, and six months of radiation treatment, respectively. RPA analysis resulted in three classes; class I included patients with Karnofsky Performance Status (KPS) ≥80. Class II included patients with KPS <80 and radioresistant or favorable histologies. Class III included all other histologies. Median survival in months was 11.4, 6.3, and 2.0, respectively. Conclusion: We developed a stratification schema predictive of survival in patients with spine metastasis. This RPA classification should be validated in independent patient populations from several institutions and may ultimately identify patients who are good candidates for more complex treatment regimens, such as stereotactic body radiotherapy.

Time to administration of stereotactic radiosurgery to the cavity after surgery for brain metastases: a real-world analysis.

Publications on adjuvant stereotactic radiosurgery (SRS) are largely limited to patients completing SRS within a specified time frame. The authors assessed real-world local recurrence (LR) for all brain metastasis (BM) patients referred for SRS and identified predictors of SRS timing. The authors retrospectively identified BM patients undergoing resection and referred for SRS between 2012 and 2018. Patients were categorized by time to SRS, as follows: 1) ≤ 4 weeks, 2) > 4-8 weeks, 3) > 8 weeks, and 4) never completed. The relationships between timing of SRS and LR, LR-free survival (LRFS), and survival were investigated, as well as predictors of and reasons for specific SRS timing. In a cohort of 159 patients, the median age at resection was 64.0 years, 56.5% of patients were female, and 57.2% were in recursive partitioning analysis (RPA) class II. The median preoperative tumor diameter was 2.9 cm, and gross-total resection was achieved in 83.0% of patients. All patients were referred for SRS, but 20 (12.6%) did not receive it. The LR rate was 22.6%, and the time to SRS was correlated with the LR rate: 2.3% for patients receiving SRS at ≤ 4 weeks postoperatively, 14.5% for SRS at > 4-8 weeks (p = 0.03), and 48.5% for SRS at > 8 weeks (p < 0.001). No LR difference was seen between patients whose SRS was delayed by > 8 weeks and those who never completed SRS (48.5% vs 50.0%; p = 0.91). A similar relationship emerged between time to SRS and LRFS (p < 0.01). Non-small cell lung cancer pathology (p = 0.04), earlier year of treatment (p < 0.01), and interval from brain MRI to SRS (p < 0.01) were associated with longer intervals to SRS. The rates of receipt of systemic therapy also differed significantly between patients by category of time to SRS (p = 0.02). The most common reasons for intervals of > 4-8 weeks were logistic, whereas longer delays or no SRS were caused by management of systemic disease or comorbidities. Available data on LR rates after adjuvant SRS are often obtained from carefully preselected patients receiving timely treatment, whereas significantly less information is available on the efficacy of adjuvant SRS in patients treated under "real-world" conditions. Management of these patients may merit reconsideration, particularly when SRS is not delivered within ≤ 4 weeks of resection. The results of this study indicate that a substantial number of patients referred for SRS either never receive it or are treated > 8 weeks postoperatively, at which time the SRS-treated patients have an LR risk equivalent to that of patients who never received SRS. Increased attention to the reasons for prolonged intervals from surgery to SRS and strategies for reducing them is needed to optimize treatment. For patients likely to experience delays, other radiotherapy techniques may be considered.

Salvage Boron Neutron Capture Therapy for Malignant Brain Tumor Patients in Compliance with Emergency and Compassionate Use: Evaluation of 34 Cases in Taiwan.

Simple SummaryAlthough boron neutron capture therapy (BNCT) is a promising therapeutic approach for malignant brain tumors, the optimal BNCT parameters for patients with life-threatening, end-stage brain tumors remain unclear. The results of this study show that for life-threatening, end-stage brain tumor patients, BNCT is a promising therapeutic modality that is associated with an overall survival time of 7.25 months and no severe adverse events (grade ≥ 3). Remarkably, patients who achieved a complete response had overall survival times and cancer-specific survival times of up to 17.66 and 22.5 months, respectively. In addition, since these patients are usually physically weak and already on the verge of life-threatening conditions, reducing the BNCT dose still has good therapeutic outcomes. Statistical analysis revealed the optimal BNCT parameters and tumor characteristics, including a tumor-to-normal tissue (T/N) uptake ratio of ≥4, a tumor volume of <20 mL, a mean tumor dose of ≥25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. The results of this study provide a reference for other clinicians or radiation oncologists conducting BNCT treatment for such patients.Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and 18F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of 18F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan–Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival.

Clinical-radiological prognostic factors in patients with brain metastasis-A retrospective study from a tertiary care centre In Easten India

Background: Brain metastasis (BM) is the most common (MC) intracranial tumor in adults. The outcome depends upon prognostic factors (PF) and optimal use of multimodality treatment. Objectives: We aimed to know clinicoradiological PF and their correlation in BM patients. Materials and Methods: Retrospectively, 19 BM patients treated with radiotherapy (RT) for the same between January 2018 and December 2019 were selected. Details of age, sex, Karnofsky performance status (KPS), recursive partitioning analysis (RPA), primary diagnosis, histopathology report, imaging details for BM-number, size and location, extracranial metastasis (EM), and primary tumor control (PTC) status were collected from the physical records. Descriptive statistics for the categorical variables and Bi-variate Spearman correlation were used to analyze the correlation between BM size, number, type of primary (TOP) with RPA, KPS, age, gender, PTC, and EM individually using the SPSS software version 20. Results: 84.2% of patients were 1.5 cm (84.2%). EM was observed in 31.6% patients. 94.73% and 68.4% of patients received whole-brain RT and systemic treatment, respectively. The maximum duration of FU was 12 months and 78.9% of patients were lost to FU post-RT. Significant correlation was observed between BM size and RPA class, KPS (R = 0.456; P = 0.049), and TOP correlated with gender (P = 0.028) and PTC (P = 0.000). However, no significant correlation between the age, RT dose, EM, number of lesions and RPA, PS (P = 0.339). Conclusions: The presence of multiple poor PF in majority of our patients and their poor follow-up indicate inertness toward health issues. Furthermore, larger BM lesions correlated with higher RPA suggesting poor outcome, so treatment modality to be judicially selected. The positive correlation between gender, PTC and primary cancer, and their prognostic role in BM should be validated in the larger studies.

Cumulative Intracranial Tumor Volume as a Prognostic Factor in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery.

Approximately 25-35% of all cancer patients suffer from brain metastases (BM), and many of them-in particular, those with a limited number of intracranial tumors-are treated with stereotactic radiosurgery (SRS). Accurate prediction of survival remains a key clinical challengein this population. Several prognostic scales have been developed to facilitate this prognostication, including the Recursive Partitioning Analysis (RPA) classification, the modified Recursive Partitioning Analysis (mRPA) subclassifications, the Basic Score for Brain Metastases (BS-BM), the Score Index for Radiosurgery (SIR), the Graded Prognostic Assessment (GPA), and the diagnosis-specific Graded Prognostic Assessment (dsGPA). However, none of these scales include consideration of the cumulative intracranial tumor volume (CITV), which is defined as the sum of all intracranial tumor volumes. Since there is mounting evidence that the CITV carries significant prognostic value in SRS-treated patients with BM, this variableshould be consideredduring survival prognostication, along with other pertinent clinical, pathological, and molecular characteristics.

The Concordance of Recursive Partitioning Analysis (RPA) Class Stratification with Survival of Brain Metastases Patients in Mohammad Hoesin Hospital, Palembang, Indonesia

A B S T R A C TIntroduction: Recursive Partitioning Analysis is one of prognostic scores, has beenvalidated to any different setting. Objective: To identify the concordance of RecursivePartitioning Analysis stratification in survival with brain metastases patients.Methods: Retrospective study was performed on brain metastases patients fromJanuary 2017 until Desember 2019 based on medical record. The follow up timestarted from the first diagnosis of brain metastases to death or last follow up. TheKaplan Meier was used to plot survival curves and the log-rank test was used toanalyse differences between groups Results: Mean overall survival time was 4,67months with 1,14 months for median survival for all patients. According to scoring,mostly (80,8%) patients were in group 3. The median survival time was 7 monthsand 2 months for group 2 and 3. Conclusion: It has shown relatively congruitysurvival in BM patients with stratification of Recursive Partitioning Analysis in ourinstitution.

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged.

Simple SummaryAlthough multiple meta-analyses on active specific immunotherapy treatment for glioblastoma multiforme (GBM) have demonstrated a significant prolongation of overall survival, no single research group has succeeded in demonstrating the efficacy of this type of treatment in a prospective, double-blind, placebo-controlled, randomized clinical trial. In this paper, we explain how the complexity of the tumor biology and tumor–host interactions make proper stratification of a control group impossible. The individualized characteristics of advanced therapy medicinal products for immunotherapy contribute to heterogeneity within an experimental group. The dynamics of each tumor and in each patient aggravate comparative stable patient groups. Finally, combinations of immunotherapy strategies should be integrated with first-line treatment. We illustrate the complexity of a combined first-line treatment with individualized multimodal immunotherapy in a group of 70 adults with GBM and demonstrate that the integration of immunogenic cell death treatment within maintenance chemotherapy followed by dendritic cell vaccines and maintenance immunotherapy might provide a step towards improving the overall survival rate of GBM patients.Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor–host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor–host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.